Malignant pleural mesothelioma (MPM) is a malignant tumor with strong invasiveness, low survival rate and lack of effective treatment options. As the only first-line treatment plan for the advanced ...MPM, combination of pemetrexed and cisplatin chemotherapy have been existing since the last 20 years. Immunotherapy has long been considered as a potential treatment plan for MPM, mainly including immune checkpoint inhibitors (ICIs), immunotoxin therapy, anti-cancer vaccine and adoptive T-cell therapy. This review focuses on summarizing the current research status of immune checkpoint inhibitors in MPM, discusses the effect of tumor heterogeneity on ICIs treatment, and describes that the biomarker-oriented immunotherapy is a new vision for the realization of individualized treatment of MPM. .
Synapse loss is one of the most critical features in Alzheimer's disease (AD) and correlates with cognitive decline. Astrocytes mediate synapse elimination through multiple EGF-like domains 10 ...(MEGF10) pathways in the developing and adult brain to build the precise neural connectivity. However, whether and how astrocytes mediate synapse loss in AD remains unknown. We here find that the phagocytic receptor MEGF10 of astrocytes is significantly increased in vivo and in vitro, which results in excessive engulfment of synapses by astrocytes in APP/PS1 mice. We also observe that the astrocytic lysosomal-associated membrane protein 1 (LAMP1) is significantly elevated, colocalized with the engulfed synaptic puncta in APP/PS1 mice, and astrocytic lysosomes contain more engulfed synaptic puncta in APP/PS1 mice relative to wild type mice. Together, our data provide evidence that astrocytes excessively engulf synapses in APP/PS1 mice, which is mediated by increased MEGF10 and activated lysosomes. The approach targeting synapse engulfment pathway in astrocytes would be a potent therapy for AD.
We synthesized a series of quinazolinone derivates as tyrosinase inhibitors and evaluated their inhibition constants. We synthesized 2-(2,6-dimethylhepta-1,5-dien-1-yl)quinazolin-4(3H)-one (Q1) from ...the natural citral. The concentration, which led to 50% activity loss of Q1, was 103 ± 2 μM (IC50 = 103 ± 2 μM). Furthermore, we considered Q1 to be a mixed-type and reversible tyrosinase inhibitor, and determined the KI and KIS inhibition constants to be 117.07 μM and 423.63 μM, respectively. Our fluorescence experiment revealed that Q1 could interact with the substrates of tyrosine and L-DOPA in addition to tyrosinase. Molecular docking studies showed that the binding of Q1 to tyrosinase was driven by hydrogen bonding and hydrophobicity. Briefly, the current study confirmed a new tyrosinase inhibitor, which is expected to be developed into a novel pigmentation drug.
Serratia marcescens, as a Gram-negative opportunistic pathogen, is a rare cause of peritonitis and has worse clinical outcomes than Gram-positive peritonitis. In this case report, we describe a case ...of Serratia marcescens associated peritonitis that was successfully cured without catheter removal. A 40-year-old male patient with peritoneal dialysis who worked in the catering industry was admitted to the hospital for 16 hours after the discovery of cloudy peritoneal dialysate and abdominal pain. Ceftazidime and cefazolin sodium were immediately given intravenously as an empirical antibiotic regimen. After detecting Serratia marcescens in the peritoneal diasate culture, the treatment was switched to ceftazidime and levofloxacin. The routine examination of peritoneal dialysate showed a significant decrease in white blood cells, the peritoneal dialysate became clear, and the peritoneal dialysis catheter was retained. The patient was treated for 2 weeks and treated with oral antibiotics for 1 week. It is necessary to further strengthen the hygiene of work environment to prevent Serratia marcescens infection in peritoneal dialysis patients. We recommend that patients with Serratia marcescens associated peritonitis should be treated with a combination of antibiotics as early as possible empirically, and at the same time, the peritoneal dialysis fluid culture should be improved, and the antibiotic regimen should be timely adjusted according to the drug sensitivity results. For patients with clinical symptoms for more than 3 days, considering the strong virulence of Serratia marcescens, whether to use meropenem directly or not can provide a reference for clinical decision-making. Further clinical studies are needed to achieve more precise anti-infective treatment.
Pyranoquinolinones synthesized from citral were used for Cu-catalyzed N-arylation with a wide range of arylboric acids. The reaction proceeded well with a broad substrate scope, providing a direct ...way to access highly functional pyranoquinolinone core structure derivatives in yields of up to 80%. Compared to citral, the compounds we obtained have a much better inhibitory effect on HeLa cervical cancer cells, and compound 3p has an IC50 value of 4.6 μM, lower than cisplatin’s 5.9 μM.
Our pilot studies have shown that clemastine fumarate (CLE) can protect against myocardial ischemia-reperfusion injury (MIRI) through regulation of toll like receptor 4 (TLR4). However, the ...protective mechanism of CLE and related signaling pathways for MIRI remains unclear. The objective of this study is to determine the mechanism by which CLE relieves MIRI in cardiomyocytes and its relationship with the TLR4/PI3K/Akt signaling pathway. CCK8 analysis was used to test the optimal concentration of TLR4 inhibitor CLI-095 and TLR4 agonist lipopolysaccharide (LPS) on MIRI. The expression of inflammatory factors, oxidative stress response, cell damage, and intracellular calcium redistribution of cardiomyocytes were examined using the ELISA kits, Total Superoxide Dismutase Assay Kit with WST-8 and Lipid Peroxidation MDA Assay Kit, LDH Cytotoxicity Assay Kit, and laser scanning confocal microscope. The expression of TLR4/PI3K/Akt and cleaved caspase-3 were determined by Western blotting and immunofluorescent staining. Our results showed that MIRI aggravated the inflammatory response, oxidative stress, cellular damage of cardiomyocytes, and caused redistribution of intracellular calcium, upregulated the expression of TLR4 protein, cleaved caspase-3 protein, and down-regulated the expression of PI3K/Akt protein. After treatment with CLE, the inflammatory response, oxidative stress, and cellular damage of cardiomyocytes were alleviated, and intracellular calcium ion accumulation decreased. The expression of TLR4 protein, cleaved caspase-3 protein declined, but PI3K/Akt protein expression increased in cardiomyocytes treated with CLE. In addition, after treatment with the TLR4 inhibitor CLI-095, the results were similar to those of CLE treatment. The TLR4 agonist LPS aggravated the reactions caused by MIRI. The role of LPS was reversed after CLE treatment. These results suggested that CLE can attenuate MIRI by activating the TLR4/PI3K/Akt signaling pathway.
The essence of plant ecological stoichiometry is to study the relationships between species and their environment, including nutrient absorption, utilization and cycling processes as well as the ...nutrient limitation of plants. Plants can regulate nutrient elements and adapt to environmental changes. To understand the adaptation mechanism, it is important to take plants as a whole and quantify the correlation between the chemometrics of different organs. Ammopiptanthus mongolicus is within the second-class group of rare−endangered plants in China and is the only evergreen broad-leaved shrub in desert areas. We analyzed the ecological stoichiometric characteristics of leaves, stems, roots, flowers and seeds of A. mongolicus in five habitats, namely fixed sandy land, semi-fixed sandy land, stony−sandy land, alluvial gravel slope and saline−alkali land. We found that (1) the nutrient contents of N, P and K were in the order of seed > flower > leaf > root > stem. The enrichment of the N, P and K in the reproductive organs promoted the transition from vegetative growth to reproductive growth. Additionally, (2) the contents of C, N, P and K and their stoichiometric ratios in different organs varied among different habitat types. The storage capacity of C, N and P was higher in sandy soil (fixed and semi-fixed sandy land), whereas the content of K was higher in gravelly soil (stony−sandy land and alluvial gravel slope), and the C:N, C:P and N:P were significantly higher in gravelly soil than those in sandy soil. A. mongolicus had higher nutrient use efficiency in stony−sandy land and alluvial gravel slope. Furthermore, (3) the C:N and N:P ratios in each organ were relatively stable among different habitats, whereas the K:P ratio varied greatly. The N:P ratios of leaves were all greater than 16 in different habitats, indicating that the growth was mainly limited by P. Moreover, (4) except for the P element, the content of each element and its stoichiometric ratio were affected by the interaction between organs and habitat. Habitat had a greater impact on C content, whereas organs had a greater influence on N, P and K content and C:N, C:P, C:K and N:P.
Myocardial ischemia-reperfusion injury (MIRI) is the most common cause of death worldwide. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the ...inflammatory response to MIRI. Dexmedetomidine (DEX), a specific agonist of α2-adrenergic receptor, is commonly used for sedation and analgesia in anesthesia and critically ill patients. Several studies have shown that dexmedetomidine has a strong anti-inflammatory effect in many diseases. Here, we investigated whether dexmedetomidine protects against MIRI by inhibiting the activation of the NLRP3 inflammasome in vitro.
We established an MIRI model in cardiomyocytes (CMs) alone and in coculture with cardiac fibroblasts (CFs) by hypoxia/reoxygenation (H/R) in vitro. The cells were treated with dexmedetomidine with or without MCC950 (a potent selective NLRP3 inhibitor). The beating rate and cell viability of cardiomyocytes, NLRP3 localization, the expression of inflammatory cytokines and NLRP3 inflammasome-related proteins, and the expression of apoptosis-related proteins, including Bcl2 and BAX, were determined.
Dexmedetomidine treatment increased the beating rates and viability of cardiomyocytes cocultured with cardiac fibroblasts. The expression of the NLRP3 protein was significantly upregulated in cardiac fibroblasts but not in cardiomyocytes after H/R and was significantly attenuated by dexmedetomidine treatment. Expression of the inflammatory cytokines IL-1β, IL-18 and TNF-α was significantly increased in cardiac fibroblasts after H/R and was attenuated by dexmedetomidine treatment. NLRP3 inflammasome activation induced the increased expression of cleaved caspase1, mature IL-1β and IL-18, while dexmedetomidine suppressed H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. In addition, dexmedetomidine reduced the expression of Bcl2 and BAX in cocultured cardiomyocytes by suppressing H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts.
Dexmedetomidine treatment can suppress H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts, thereby alleviating MIRI by inhibiting the inflammatory response.
The vascular bundles of rice panicles serve to connect the source and the sink, as well as serving as a channel for the transportation of materials. In this study, two homozygous japonica rice ...strains were used as materials. The vascular bundle structures of the branches in different positions within a rice panicle were observed, and their cross-sectional areas were calculated. In addition, the ultrastructure of the central large vascular bundle (LVB) phloem in the rachillae of superior spikelets (SS) and inferior spikelets (IS) was observed during the grain filling period. Moreover, the soluble sugar and protein contents of the SS and IS rachillae were also measured to study whether the differences in the structure of vascular bundles of the branches were related to the plumpness of grain at different positions. The results showed that vascular bundle cross-sectional areas of the basal primary branches were greater than those in the upper primary branches. Moreover, there was little difference in the areas of vascular bundles between the basal secondary branches and upper secondary branches. However, the vascular bundle areas of the IS rachillae were lower than those in the SS rachillae. Therefore, we believe that the poor vascular tissue channel of the IS rachillae could be the limiting factor in IS plumpness. The results also showed that a similar time course in the degradation pattern of some organelles of the sieve elements and companion cells in central LVB was observed in the SS rachillae and IS rachillae during the grain filling period. Compared with the IS rachillae, more abundant mitochondria and plasmodesmata were found in the companion cells of SS rachillae at the beginning of the filling stage, while no significant differences between SS and IS rachillae were identified at the middle and late filling stages, which implies that the SS rachillae were relatively more effective at transportation compared with the IS rachillae at the initial filling stage. Therefore, the undeveloped vascular bundles of the IS rachillae and their poor physiology and lack of ability to transport at the initial filling stages could be the limiting factor in IS plumpness.
We developed a microfluidic chip integrated with nucleic acid purification and droplet-based digital polymerase chain reaction (ddPCR) modules to realize a 'sample-in, result-out' infectious virus ...diagnosis. The whole process involved pulling magnetic beads through drops in an oil-enclosed environment. The purified nucleic acids were dispensed into microdroplets by a concentric-ring, oil-water-mixing, flow-focusing droplets generator driven under negative pressure conditions. Microdroplets were generated with good uniformity (CV = 5.8%), adjustable diameters (50-200 μm), and controllable flow rates (0-0.3 μL/s). Further verification was provided by quantitative detection of plasmids. We observed a linear correlation of R
= 0.9998 in the concentration range from 10 to 10
copies/μL. Finally, this chip was applied to quantify the nucleic acid concentrations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The measured nucleic acid recovery rate of 75 ± 8.8% and detection limit of 10 copies/μL proved its on-chip purification and accurate detection abilities. This chip can potentially be a valuable tool in point-of-care testing.
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